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May 1, 2020

Hydroxychloroquine, Coronavirus Disease 2019, and QT Prolongation

Author Affiliations
  • 1Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 2Duke Clinical Research Institute, Durham, North Carolina
  • 3Duke University, Durham, North Carolina
  • 4Stanford University School of Medicine, Stanford, California
  • 5Center for Digital Health, Stanford University School of Medicine, Stanford, California
  • 6Veterans Affairs Palo Alto Health Care System, Palo Alto, California
  • 7Editor, JAMA Cardiology
  • 8Associate editor, JAMA Cardiology
JAMA Cardiol. Published online May 1, 2020. doi:10.1001/jamacardio.2020.1782

The complex decisions facing clinical teams caring for patients who are critically ill with coronavirus disease 2019 (COVID-19) are compounded by the absence of proven treatment strategies. Lacking robust trial evidence, clinicians are forced to consider all options based on preclinical and small observational studies, often in heart-wrenching settings of patients who are deteriorating in the throes of severe pneumonia, acute respiratory distress syndrome, cytokine storm, and in many cases, cardiovascular complications.

Among possible therapies, hydroxychloroquine has been advocated and even politicized as a promising therapy because of its anti-inflammatory and potential antiviral properties. The drug, known for its immunosuppressive and antimalarial effects, has risen to the top of many treatment algorithms alone or in combination with azithromycin. Hydroxychloroquine was first approved in 1955 by the US Food and Drug Administration and has been viewed as generally safe and well-tolerated in patients treated for chronic inflammatory conditions. However, hydroxychloroquine prolongs the QT interval because of blockade of inward cellular potassium current and has a known risk of proarrhythmia,1-3 especially in the setting of other drugs that also prolong the QT interval. Drug-induced QT prolongation has long been considered a surrogate for risk of drug-associated torsades de pointes.4 Although widely used, azithromycin has also been increasingly recognized for risks of QT interval prolongation and sudden death.5 Opinions vary regarding the optimal dose of hydroxychloroquine and stopping points based on corrected QT (QTc) prolongation. In patients with COVID-19, there may be greater risk tolerance among clinicians for QTc prolongation and toxicity in patients who are very sick, but at the same time, there may be an increased risk of ventricular arrhythmias because of electrolyte abnormalities, hypoxia, concomitant QT-prolonging medications, and underlying cardiovascular disease.6,7 The risk-benefit trade off of hydroxychloroquine may also depend on whether other drugs with unclear benefit (such as remdesivir and tocilizumab) are available as alternative therapies.